DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 1, 18, 19, 42-53, & 68 filed on 08/27/2026 are pending. Claim 158 is withdrawn from consideration as being drawn to a non-elected invention. Claims 1, 42, 43, 45, 48, & 68 are currently under examination directed to the elected species of the combination of C1orf226, TMEM92, LINC00482, MMP9, CD163, has-miR-3918, AK5, MICU3, CD200, and has-miR-760 in claims 1, 42, 43, & 68, of chemotherapy in claim 45, and of whole blood in claim 48 (see response dated 01/29/2026). The cancellation of claims 2-4 in the reply filed on 08/27/2026 is acknowledged. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 101
Claims 1, 18, 19, 42-45, & 48-53 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method for treating a subject with GBM. The claimed invention also recites treating the subject for GBM after the expression level of one or more biomarkers have been determined in a sample of the subject which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of treating the subject for GBM after the expression level of one or more biomarkers has been determined in a sample from the subject, however, this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the steps of expression level of one or more biomarkers have been determined are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than an abstract idea and any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that the claim simply recited administering a treatment to a patient after levels of a biomarker have been determined in the patient and there is no recitation of a correlation between levels of the biomarker and the detection of the GBM illness and therefore there is no purely mental or cognitive step in the claim and, accordingly, the claim is not directed to an abstract idea. Further, the response asserts that this position is directly supported by the USPTO’S Subject Matter Example 29 in which Example 29 claim 1 recited a method of detecting JUL-1 in a patient comprising detecting whether the biomarker JUL-1 is present. Further, the response asserts the instant claim 1 is analogous to the eligible claim 1 of example 29 and instant claim 1 recites a method of treating a subject for GBM after expression levels of specified biomarkers have been determined in a sample from the subject, and critically, instant claim 1 does not recite diagnosing GBM based on the determined expression levels, drawing any correlation between the expression levels and a disease state, or making any mental determination as to whether a patient has GBM. Further, the response asserts that the claim requires only that the biomarker levels have been determined (a physical laboratory step) and that treatment is administered thereafter which is precisely the type of claim that the USPTO’s own guidance holds is not directed to a judicial exception under Step 2A, Prong 1. This argument has been thoroughly reviewed but was not found persuasive. First, claim 1 as currently amended, was not found to recite a natural correlation and instead, as discussed further above and previously, the claimed invention recites treating the subject for GBM after the expression level of one or more biomarkers have been determined in a sample of the subject which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions. Second, Example 29 claim 1 of USPTO’s Subject Matter Examples is not analogous to instant claim 1 as currently amended. Example 29 claim 1 of USPTO’s Subject Matter Examples recites the physical step of “detecting” whereas instant claim 1 as currently amended recites the biomarkers “have been determined” in which determined is the recitation of an abstract ideas because it encompasses conclusions, evaluations, observations, and determinations which can occur entirely within the mind (See MPEP 2106.04(a)(2)(III)).
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 1, 44, 48, 50-52, & 68 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maachani (Maachani et al.; OncoTarget, Vol. 7, pages 52912-52927, May 2015), in view of Dong (Dong et al.; International Journal of Oncology, Vol. 45, pages 746-756, April 2014), as cited on the IDS dated 09/06/2023.
Regarding amended claim 1, Maachani teaches treatment of glioblastoma (GBM) samples comprising measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array, in which the Affymetrix HuEx-1_0-st-v2 array comprises oligonucleotides that measure the expression of genes including MMP9, TMEM92, C1orf226, CD163, LINC00482, AK5, CD200, and MICU3 (the expression level of one or more biomarkers of MMP9, TMEM92, C1orf226, CD163, LINC00482, AK5, CD200, and MICU3 has been determined in a sample from the subject) (pg. 52913 column 1 2nd full paragraph lines 14-22; pg. 52917 paragraph bridging column 1 & 2 lines 5-11; pg. 52923 paragraph bridging column 1 & 2 lines 1-40; pg. 52924 paragraph bridging column 1 & 2 lines 1-10).
Maachani does not teach the expression level of miR-3918 or miR-760 has been determined in a sample from the subject.
Dong teaches that miRNAs are frequently dysregulated in GBM patients and analysis of miRNAs in the serum of patients with GBM through microarray analysis to determine differentially expressed miRNAs in serum between the GBM and normal controls with the Human panelI+II v3 miRCURY LNATM Universal RT miRNA PCR array in which this miRNA PCR array comprises targets for miR-3918 and miR-760 (the expression level of one or more biomarkers of miR-3918 and miR-760 has been determined in a sample from the subject) (abstract lines 1-10; pg. 746-747 paragraph bridging pg. 746 & 747 lines 1-6; pg. 747 column 1 1st full paragraph lines 1-7; pg. 747 column 1 2nd full paragraph lines 1-10). In addition, Dong teaches that analysis of miRNA profiles in the blood may serve as a new biomarker for glioma diagnosis with high specificity and sensitivity (abstract lines 19-22).
Maachani and Dong are considered to be analogous to the claimed invention because they are all in the same field of measuring the expression levels of biomarkers in GBM samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array in Maachani to incorporate the measurement of differentially expressed miRNAs in serum between the GBM and normal controls with the Human panelI+II v3 miRCURY LNATM Universal RT miRNA PCR array as taught in Dong because Dong teaches that doing so would provide a method to analyze miRNA profiles in blood to serve as a new biomarker for glioma diagnosis with high specificity and sensitivity.
Regarding claim 44, Maachani teaches treatment of glioblastoma (GBM) samples comprising measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array (subject is treated for GBM) (pg. 52913 column 1 2nd full paragraph lines 14-22; pg. 52917 paragraph bridging column 1 & 2 lines 5-11; pg. 52923 paragraph bridging column 1 & 2 lines 1-40; pg. 52924 paragraph bridging column 1 & 2 lines 1-10).
Regarding claim 48, Dong teaches the sample comprises a blood sample from GBM patients and healthy controls (sample from the subject comprises a whole blood sample) (pg. 746-747 paragraph bridging pg. 746 & 747 lines 1-6).
Regarding claim 50, Dong teaches the sample comprises a blood sample from GBM patients and healthy controls in which RNA is extracted from the sample (sample from the subject comprises nucleic acids) (pg. 746-747 paragraph bridging pg. 746 & 747 lines 1-6).
Regarding claim 51, Dong teaches the sample comprises a blood sample from GBM patients and healthy controls in which RNA is extracted from the sample (sample from the subject comprises a fractionated blood sample comprising nucleic acids) (pg. 746-747 paragraph bridging pg. 746 & 747 lines 1-6).
Regarding claim 52, Maachani teaches the subject is a human GBM patient (subject is a human subject) (pg. 52924 paragraph bridging column 1 & 2 lines 1-10).
Dong teaches the sample comprises a blood sample from GBM patients and healthy controls (sample comprises a human sample) (pg. 746-747 paragraph bridging pg. 746 & 747 lines 1-6).
Regarding claim 68, Maachani teaches treatment of glioblastoma (GBM) samples comprising measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array, in which the Affymetrix HuEx-1_0-st-v2 array comprises oligonucleotides that measure the expression of genes including MMP9, TMEM92, C1orf226, CD163, LINC00482, AK5, CD200, and MICU3 (the expression level of one or more biomarkers of MMP9, TMEM92, C1orf226, CD163, LINC00482, AK5, CD200, and MICU3 has been determined in a sample from the subject) (pg. 52913 column 1 2nd full paragraph lines 14-22; pg. 52917 paragraph bridging column 1 & 2 lines 5-11; pg. 52923 paragraph bridging column 1 & 2 lines 1-40; pg. 52924 paragraph bridging column 1 & 2 lines 1-10).
Maachani does not teach the expression level of miR-3918 or miR-760 has been determined in a sample from the subject.
Dong teaches that miRNAs are frequently dysregulated in GBM patients and analysis of miRNAs in the serum of patients with GBM through microarray analysis to determine differentially expressed miRNAs in serum between the GBM and normal controls with the Human panelI+II v3 miRCURY LNATM Universal RT miRNA PCR array in which this miRNA PCR array comprises targets for miR-3918 and miR-760 (the expression level of one or more biomarkers of miR-3918 and miR-760 has been determined in a sample from the subject) (abstract lines 1-10; pg. 746-747 paragraph bridging pg. 746 & 747 lines 1-6; pg. 747 column 1 1st full paragraph lines 1-7; pg. 747 column 1 2nd full paragraph lines 1-10). In addition, Dong teaches that analysis of miRNA profiles in the blood may serve as a new biomarker for glioma diagnosis with high specificity and sensitivity (abstract lines 19-22).
Maachani and Dong are considered to be analogous to the claimed invention because they are all in the same field of measuring the expression levels of biomarkers in GBM samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array in Maachani to incorporate the measurement of differentially expressed miRNAs in serum between the GBM and normal controls with the Human panelI+II v3 miRCURY LNATM Universal RT miRNA PCR array as taught in Dong because Dong teaches that doing so would provide a method to analyze miRNA profiles in blood to serve as a new biomarker for glioma diagnosis with high specificity and sensitivity.
Claim(s) 18, 42, 49, & 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maachani (Maachani et al.; OncoTarget, Vol. 7, pages 52912-52927, May 2015) and Dong (Dong et al.; International Journal of Oncology, Vol. 45, pages 746-756, April 2014), as cited on the IDS dated 09/06/2023, as applied to claims 1, 44, 48, 50-52, & 68 above, and further in view of Xue (Xue et al.; Oncology Letters, Vol. 13, pages 1325-1330, November 2016).
The teachings of Maachani and Dong with respect to claim 1 are discussed above.
Regarding amended claim 18, Maachani and Dong does not teach the expression level of one or more biomarkers in the sample were determined to be increased compared to levels of expression in samples from subjects identified as not having GBM, identified as low risk, or normal tissues.
Xue teaches measuring expression levels of MMP9 in glioblastoma samples and that expression levels of MMP9 was increased in glioma between tumor grades (one or more biomarkers comprising MMP9 is increased compared to subject identified as low risk) (abstract lines 1-18; pg. 1326 column 1 1st full paragraph lines 1-9; pg. 1326 column 1 2nd full paragraph lines 1-5; pg. 1326-1328 paragraph bridging pg. 1327 & 1328 lines 1-17). Xue also teaches that measuring expression levels of MMP9 in glioma can provide information on disease progression (abstract lines 23-27).
Maachani, Dong, and Xue are considered to be analogous to the claimed invention because they are all in the same field of measuring expression levels of biomarkers in GMB samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array in Maachani to incorporate the determining increased expression of MMP9 (one or more biomarkers determined to be increased) as taught in Xue because Xue teaches that doing so would provide a method to determine information on disease progression in glioblastoma samples.
Regarding amended claim 42, Maachani and Dong does not teach the expression level of MMP9 were determined to be increased compared to levels of expression in samples from subjects identified as not having GBM, identified as low risk, or normal tissues.
Xue teaches measuring expression levels of MMP9 in glioblastoma samples and that expression levels of MMP9 was increased in glioma between tumor grades (MMP9 is increased compared to subject identified as low risk) (abstract lines 1-18; pg. 1326 column 1 1st full paragraph lines 1-9; pg. 1326 column 1 2nd full paragraph lines 1-5; pg. 1326-1328 paragraph bridging pg. 1327 & 1328 lines 1-17). Xue also teaches that measuring expression levels of MMP9 in glioma can provide information on disease progression (abstract lines 23-27).
Maachani, Dong, and Xue are considered to be analogous to the claimed invention because they are all in the same field of measuring expression levels of biomarkers in GMB samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array in Maachani to incorporate the determining increased expression of MMP9 as taught in Xue because Xue teaches that doing so would provide a method to determine information on disease progression in glioblastoma samples.
Regarding claim 49, it is noted that claim 18, from which claim 49 depends from, recites determining expression levels of one or more biomarkers in the sample determined to be increased compared to levels of expression in samples from subjects identified as not having GBM, subjects identified as low risk, or normal tissues or within the range of expression levels in samples of subjects identified as having GBM or identified as high risk. Therefore, claim 18 and dependent claim 49 do not require the use of normal tissues.
Maachani teaches analyzing differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array (determining differential expression levels in samples with GBM compared to control (determining expression level of biomarkers in the sample within range of expression levels in samples of subjects identified as having GBM or identified as high risk)) (pg. 52924 paragraph bridging column 1 & 2 lines 1-10).
Regarding amended claim 53, Dong teaches the sample comprises a blood sample from GBM patients and healthy controls without GBM (sample from subjects identified as not having GBM comprises samples from subjects without GBM) (pg. 746-747 paragraph bridging pg. 746 & 747 lines 1-6).
Claim(s) 19 & 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maachani (Maachani et al.; OncoTarget, Vol. 7, pages 52912-52927, May 2015) and Dong (Dong et al.; International Journal of Oncology, Vol. 45, pages 746-756, April 2014), as cited on the IDS dated 09/06/2023, as applied to claims 1, 44, 48, 50-52, & 68 above, and further in view of Zhang (Zhang et al.; Cancer Science, Vol. 111, pages 2413-2422, April 2020).
The teachings of Maachani and Dong with respect to claim 1 are discussed above.
Regarding amended claim 19, Maachani and Dong does not teach the expression level of one or more biomarkers in the sample were determined to be decreased compared to levels of expression in samples from subjects identified as not having GBM, identified as low risk, or normal tissues.
Wang teaches measuring microRNA expression in GBM samples comprising measuring a reduced (decreased) expression of miR-760 in GBM samples compared to normal brain samples (one or more biomarkers comprising miR-760 is decreased compared to normal tissue) (abstract lines 11-16; pg. 2418-2420 paragraph bridging pg. 2418 & 2420 lines 13-16; Figure 5). Zhang also teaches that this method enables determination of diagnostic biomarkers and therapeutic targets for treatment of GBM (pg. 2421 column 1 1st full paragraph lines 1-7).
Maachani, Dong, and Zhang are considered to be analogous to the claimed invention because they are all in the same field of measuring expression levels of biomarkers in GMB samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measurement of differentially expressed miRNAs in serum between the GBM and normal controls with the Human panelI+II v3 miRCURY LNATM Universal RT miRNA PCR array in Dong to incorporate the determining decreased expression of miR-760 (one or more biomarkers determined to be decreased) as taught in Zhang because Zhang teaches that doing so would enables determination of diagnostic biomarkers and therapeutic targets for treatment of GBM.
Regarding amended claim 43, Maachani and Dong does not teach the expression level of miR-760 were determined to be decreased compared to levels of expression in samples from subjects identified as not having GBM, identified as low risk, or normal tissues.
Wang teaches measuring microRNA expression in GBM samples comprising measuring a reduced (decreased) expression of miR-760 in GBM samples compared to normal brain samples (one or more biomarkers comprising miR-760 is decreased compared to normal tissue) (abstract lines 11-16; pg. 2418-2420 paragraph bridging pg. 2418 & 2420 lines 13-16; Figure 5). Zhang also teaches that this method enables determination of diagnostic biomarkers and therapeutic targets for treatment of GBM (pg. 2421 column 1 1st full paragraph lines 1-7).
Maachani, Dong, and Zhang are considered to be analogous to the claimed invention because they are all in the same field of measuring expression levels of biomarkers in GMB samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measurement of differentially expressed miRNAs in serum between the GBM and normal controls with the Human panelI+II v3 miRCURY LNATM Universal RT miRNA PCR array in Dong to incorporate the determining decreased expression of miR-760 as taught in Zhang because Zhang teaches that doing so would enables determination of diagnostic biomarkers and therapeutic targets for treatment of GBM.
Claim(s) 45-47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maachani (Maachani et al.; OncoTarget, Vol. 7, pages 52912-52927, May 2015), Dong (Dong et al.; International Journal of Oncology, Vol. 45, pages 746-756, April 2014), as cited on the IDS dated 09/06/2023, and Xue (Xue et al.; Oncology Letters, Vol. 13, pages 1325-1330, November 2016), as applied to claims 18, 42, 49, & 53 above, and further in view of Wang (Wang et al.; EBioMedicine, Vol. 37, pages 68-77, October 2018), as cited on the IDS dated 09/06/2023, as evidenced by Kanzawa (Kanzawa et al.; British Journal of Cancer, Vol. 89, pages 922-929, 2003).
The teachings of Maachani, Dong, and Xue with respect to claim 18 are discussed above.
Regarding claims 45-47, Maachani, Dong, and Xue does not teach that the treatment comprises treatment with the chemotherapy temozolomide.
Wang teaches measuring expression of biomarkers with a microarray in GBM patients and then treating GBM cell lines with temozolomide (treatment for GBM comprises treatment with chemotherapy temozolomide), in which temozolomide can be administered orally as evidenced by Kanzawa (pg. 922 column 1 1st full paragraph lines 1-5 of Kanzawa) (abstract background lines 1-3; abstract methods lines 1-5; pg. 69-70 paragraph bridging pg. 69 & 70 lines 1-8; pg. 74-75 paragraph bridging pg. 74 & 75 lines 1-8). In addition, this method provides new insights to early diagnosis and the prognosis for GBM patients and provides potential GM therapeutic targets to treat GBM (abstract interpretation lines 1-3).
Maachani, Dong, Xue, and Wang are considered to be analogous to the claimed invention because they are all in the same field of measuring the expression levels of biomarkers in GBM samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treatment of glioblastoma (GBM) samples comprising measuring differential expression of biomarkers with an array in Maachani to incorporate the treatment of GBM with the chemotherapy temozolomide as taught in Wang because Wang teaches that doing so would provide provides new insights to early diagnosis and the prognosis for GBM patients and provides potential GM therapeutic targets to treat GBM.
Response to Arguments
The response traverses the rejection. The response asserts that claim 1 recites a method of treating a patient with GBM after detecting a specific panel of biomarkers and, importantly, the specific panel of biomarkers recited in claim 1 – MMP9, TMEM92, Clorf226, CD163, LINC00482, miR-3918, AK5, CD200, MICU3, and miR-760 was not known in the art as a panel of GBM markers that can be used to identify a patient population that can benefit from treatment for GBM. Further, the response asserts that the cited art describes broad-coverage array platforms that incidentally include probes for some of these markers, but the cited art fails to disclose or suggest the combination of claimed biomarkers may identify patients conducive to GBM treatments. This argument has been thoroughly reviewed but was not found persuasive. First, as discussed further above, Maachani teaches treatment of glioblastoma (GBM) samples comprising measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array, in which the Affymetrix HuEx-1_0-st-v2 array comprises oligonucleotides that measure the expression of genes including MMP9, TMEM92, C1orf226, CD163, LINC00482, AK5, CD200, and MICU3 (the expression level of one or more biomarkers of MMP9, TMEM92, C1orf226, CD163, LINC00482, AK5, CD200, and MICU3 has been determined in a sample from the subject) (pg. 52913 column 1 2nd full paragraph lines 14-22; pg. 52917 paragraph bridging column 1 & 2 lines 5-11; pg. 52923 paragraph bridging column 1 & 2 lines 1-40; pg. 52924 paragraph bridging column 1 & 2 lines 1-10). Further, Dong teaches that miRNAs are frequently dysregulated in GBM patients and analysis of miRNAs in the serum of patients with GBM through microarray analysis to determine differentially expressed miRNAs in serum between the GBM and normal controls with the Human panelI+II v3 miRCURY LNATM Universal RT miRNA PCR array in which this miRNA PCR array comprises targets for miR-3918 and miR-760 (the expression level of one or more biomarkers of miR-3918 and miR-760 has been determined in a sample from the subject) (abstract lines 1-10; pg. 746-747 paragraph bridging pg. 746 & 747 lines 1-6; pg. 747 column 1 1st full paragraph lines 1-7; pg. 747 column 1 2nd full paragraph lines 1-10). Therefore, the combination of Maachani and Dong teaches the panel of biomarkers as recited in amended claim 1 as discussed further above.
The response also asserts that Maachani is entirely focused on examining the role of MPS1 in glioblastoma and not to detect or measure expression levels of individual gene biomarkers such as MMP9, TMEM92, Clorf226, CD163, LINC00482, AK5, CD200, or MICU3 in patient samples for selecting treatment. Further, the response asserts that the use of the Affymetrix HuEx-1_0-st-v2 array in Maachani comprising recited biomarkers is a comprehensive array and that the mere fact that such a broad array capable of detecting recited biomarkers does not mean that Maachani teaches or suggests selecting and measuring specific biomarkers as a diagnostic panel for the purpose of determining whether to treat a patient for GBM and that Maachani does not identify or disclose these biomarkers as relevant to GBM detection or treatment selection and, accordingly, Maachani does not teach the claimed step of treating a subject for GBM after expression levels of one or more of the recited biomarkers have been determined in the sample from the subject. This argument has been thoroughly reviewed but was not found persuasive. First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Second, claim 1 as currently amended recites that the biomarkers “have been determined in a sample from the subject” in which Maachani teaches treatment of glioblastoma (GBM) samples comprising measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array, in which the Affymetrix HuEx-1_0-st-v2 array comprises oligonucleotides that measure the expression of genes including MMP9, TMEM92, C1orf226, CD163, LINC00482, AK5, CD200, and MICU3 (pg. 52913 column 1 2nd full paragraph lines 14-22; pg. 52917 paragraph bridging column 1 & 2 lines 5-11; pg. 52923 paragraph bridging column 1 & 2 lines 1-40; pg. 52924 paragraph bridging column 1 & 2 lines 1-10). Therefore, as broadly recited in the claim the Affymetrix HuEx-1_0-st-v2 array determines the expression levels of recited biomarkers comprising MMP9, TMEM92, C1orf226, CD163, LINC00482, AK5, CD200, and MICU3. Therefore, Maachani teaches treating a subject for GBM after expression levels of one or more biomarkers have been determined in the sample from the subject.
The response also asserts that the mere fact that a broad-coverage miRNA array platform may include probes for miR-3918 and miR-760 does not constitute teaching to detect those specific miRNAs as biomarkers for GBM or as a basis for selecting GBM treatment and that, importantly, Dong does not single out miR-3918 or miR-760 as biomarkers of interest for GBM, does not correlate their expression levels with GBM detection or treatment, and does not suggest measuring them before treating a patient for GBM. This argument has been thoroughly reviewed but was not found persuasive. First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Second, it is noted that claim 1 as currently amend is a comprising “open” claim and therefore does not exclude determination of expression levels of other biomarkers in a sample. Further, Dong teaches that miRNAs are frequently dysregulated in GBM patients and analysis of miRNAs in the serum of patients with GBM through microarray analysis to determine differentially expressed miRNAs in serum between the GBM and normal controls with the Human panelI+II v3 miRCURY LNATM Universal RT miRNA PCR array in which this miRNA PCR array comprises targets for miR-3918 and miR-760 (the expression level of one or more biomarkers of miR-3918 and miR-760 has been determined in a sample from the subject) (abstract lines 1-10; pg. 746-747 paragraph bridging pg. 746 & 747 lines 1-6; pg. 747 column 1 1st full paragraph lines 1-7; pg. 747 column 1 2nd full paragraph lines 1-10). Therefore, Dong teaches determining miR-3918 and miR-760 in a GBM sample.
The response also asserts that there is no motivation to combine Maachani and Dong as they address entirely different scientific objectives and that the references operate in distinct fields of inquiry in intracellular signaling pathway analysis and miRNA profiling and that neither reference teaches or suggests the method recited in claim 1. Further, the response asserts that the Examiner has not articulated a rational explaining of why a person of ordinary skill in the art would have been motivated to combine the teachings of Maachani and Dong to arrive at the claimed method with a reasonable expectation of success as independent claims 1 and 68 recites a specific panel of biomarkers and no single reference discloses both the gene biomarkers and the miRNA biomarkers recited in the claims. Further, the response asserts that no single assay simultaneously detects both mRNA/gene expression and, accordingly the selection and combination of both gene biomarkers and miRNA biomarkers into a single diagnostic panel, as recited in claims 1 and 68, represented a non-obvious contribution that is not taught by Maachani or Dong, individually or in combination. This argument has been thoroughly reviewed but was not found persuasive. First, claim 1 as currently amended is rejected under 35 USC 103 as being unpatentable over Maachani in view of Dong and teachings of recitations in the claim being recited in a single reference is not a standard for consideration under 35 USC 103. Second, Maachani and Dong are not in distinct fields as Maachani and Dong are considered to be analogous to the claimed invention because they are all in the same field of measuring the expression levels of biomarkers in GBM samples. Further, one of ordinary would be motivated to combine the teachings of Maachani with the analysis of miRNA biomarkers taught in Dong as Dong teaches that analysis of miRNA profiles enables analysis of new biomarker for GBM with high specificity and sensitivity. Therefore, as discussed further above, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the differential expression of biomarkers in GBM patients with the Affymetrix HuEx-1_0-st-v2 array in Maachani to incorporate the measurement of differentially expressed miRNAs in serum between the GBM and normal controls with the Human panelI+II v3 miRCURY LNATM Universal RT miRNA PCR array as taught in Dong because Dong teaches that doing so would provide a method to analyze miRNA profiles in blood to serve as a new biomarker for glioma diagnosis with high specificity and sensitivity.
The response also asserts that claims 18, 19, 42-44, & 48-53 each depend from claim 1 and include additional limitation that further distinguish over the cited are and that these claims are rendered obvious at least for the same reasons as claim 1. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
The response also asserts that Maachani and Dong does not teach the method of claim 1 from which claims 45-47 ultimately depend and Wang and Kanzawa do not remedy these deficiencies of Maachani and Dong. This argument has been thoroughly reviewed but was not found persuasive for the reasons set for above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 1, 18, 19, 42-53, & 68 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
